Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart

Bell, James; Raaijmakers, A.; Curl, Claire L.; Reichelt, Melissa E.; Harding, T.; Bei, Aier; Ng, Dominic C.H.; Erickson, Jeffrey R.; Petroff, Martín Gerardo Vila; Harrap, Stephen; Delbridge, L.

doi:10.1016/j.ijcard.2014.11.159

Cited by 27 publications

(47 citation statements)

References 48 publications

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“…Nevertheless our observations in NRVMs confirm that there is differential activation of equivalently expressed levels of CaMKIIδ B and δ C by oxidative stress and further indicate an association between cytosolic CaMKIIδ C autophosphorylation and subsequent IκBα degradation and nuclear accumulation of p65. Notably another recent report confirmed the ability of CaMKIIδ subtypes to undergo differential posttranslational modification during reperfusion [30]. …”

Section: 7 Discussionmentioning

confidence: 80%

CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

Gray

Suetomi

Xiang

et al. 2017

Journal of Molecular and Cellular Cardiology

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Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIδ isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIδ gene deletion. In this study we sought to compare the roles of the CaMKIIδB and CaMKIIδC subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIδKO, and mice expressing only CaMKIIδB or δC were subjected to ex vivo global ischemia for 25 minutes followed by reperfusion. Infarct formation was assessed at 60 minutes reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKIIδ conferred significant protection from ex vivo I/R. Re-expression of CaMKIIδC in the CaMKIIδKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIδB was protective. Selective activation of CaMKIIδC in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and tumor necrosis factor alpha (TNF-α) expression by CaMKIIδB and CaMKIIδC. Selective activation of CaMKIIδC was also observed and associated with NF-κB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-κB or TNF-α significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIδC, demonstrating distinct roles for CaMKIIδ subtypes in I/R and implicating acute activation of CaMKIIδC and NF-κB in the pathogenesis of reperfusion injury.

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Section: 7 Discussionmentioning

confidence: 80%

CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

Gray

Suetomi

Xiang

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…Concerning changes in myocardial cell membrane ion channel structure and function, ventricular electrical remodeling is an important cause of arrhythmia following myocardial infarction (Liu and O'Rourke, 2013;Bell et al, 2015). After myocardial infarction, reentry and "abnormal automaticity" are associated with ventricular arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

Impact of citrate pretreatment on ventricular arrhythmia and myocardial capase-3 expression in ischemia/reperfusion injury

Lü¹,

Li²,

Zhou³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Ischemia/reperfusion (I/R) injury often triggers ventricular arrhythmia. Citrate binds calcium ions, forming a soluble calcium citrate complex that may reduce I/R injury by affecting calcium ion concentration. We tested the effects of citrate pretreatment on ventricular heart rate and related factors in a rat I/R model. Fifty male Sprague Dawley rats weighing 350-400 g were randomly divided into equally sized control (A), model (B), and 0.1 M (C), 0.05 M (D), and 0.025 M (E) citrate groups. An I/R model was established by ligating the left anterior descending coronary artery. Serum calcium ion concentration was measured before and after citrate treatment. Triphenyltetrazolium chloride staining and spectrophotometry were used to determine infarction area and caspase-3 protein levels in myocardial tissue, respectively. Polymerase chain reaction was performed to test myocardial calmodulin (CAM) expression. The frequency of ventricular arrhythmia in group B was significantly higher than in the sham surgery group (P < 0.05). Citrate pretreatment resulted in lower and higher frequencies than those observed in the model and control groups, respectively, in a dose-independent manner. The most obvious reduction in ventricular arrhythmia was seen in Group D. Serum calcium ion concentration decreased markedly after citrate treatment (P < 0.05), with a specific pattern emerging over time. Infarction area and caspase-3 and CAM levels were significantly lower in the citrate groups compared with the model group (P < 0.05). Citrate can reduce myocardial cell apoptosis, alleviating ventricular arrhythmia and protecting the myocardium by reducing serum calcium ion concentration and downregulating caspase-3 and CAM expression.

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“…Notably, this interpretation of CaMKII␦ action has relied on findings derived from male hearts. Very recent evidence suggests that the relative degree to which CaMKII␦ regulates SR Ca 2ϩ uptake and release mechanisms can determine whether it confers a beneficial or deleterious influence on postischemic outcomes (31,32,47). Undoubtedly, this relationship between CaMKII␦ and SR Ca 2ϩ regulation is influenced by the subcellular environment (eg, redox status) of the cardiomyocyte, although to what extent sex and sex steroids modulate CaMKII␦ responsiveness is yet to be determined.…”

Section: Is Augmented Cardiomyocyte Ca 2؉ Cycling In High Ca 2؉ /Repementioning

confidence: 99%

Myocardial and Cardiomyocyte Stress Resilience Is Enhanced in Aromatase-Deficient Female Mouse Hearts Through CaMKIIδ Activation

et al. 2015

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The role of sex steroids in cardioprotection is contentious, with large clinical trials investigating hormone supplementation failing to deliver outcomes expected from observational studies. Mechanistic understanding of androgen/estrogen myocardial actions is lacking. Using a genetic model of aromatase tissue deficiency (ArKO) in female mice, the goal of this investigation was to evaluate the capacity of a shift in cardiac endogenous steroid conversion to influence ischemia-reperfusion resilience by optimizing cardiomyocyte Ca2+ handling responses. In isolated normoxic cardiomyocytes, basal Ca2+ transient amplitude and extent of shortening were greater in ArKO myocytes, with preservation of diastolic Ca2+ levels. Isolated ArKO cardiomyocytes exposed to a high Ca2+ load exhibited greater Ca2+ transient and contractile amplitudes, associated with a greater postrest spontaneous sarcoplasmic reticulum Ca2+ load-release. Microarray differential gene expression analysis of normoxic ventricular tissues from ArKO vs wild-type identified a significant influence of aromatase on genes involved in cardiac Ca2+ handling and signaling [including calmodulin dependent kinase II (CaMKII)-δ], myofilament structure and function, glucose uptake and signaling, and enzymes controlling phosphorylation-specific posttranslational modification status. CaMKII expression was not changed in ventricular tissues, although CaMKIIδ activation and phosphorylation of downstream targets was enhanced in ArKO hearts subjected to ischemia-reperfusion. Overall, this investigation shows that relative withdrawal of estrogen in favor of testosterone through genetically induced tissue aromatase deficiency in females modifies the gene expression profile to effect inotropic support via optimized Ca2+ handling in response to stress, with a modest impact on basal function. Consideration of aromatase inhibition, acutely or chronically, may have a role in cardioprotection, of particular relevance to women.

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Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart

Cited by 27 publications

References 48 publications

CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α

Impact of citrate pretreatment on ventricular arrhythmia and myocardial capase-3 expression in ischemia/reperfusion injury

Myocardial and Cardiomyocyte Stress Resilience Is Enhanced in Aromatase-Deficient Female Mouse Hearts Through CaMKIIδ Activation

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